Cardular PP Uro

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Cardular PP Uro uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Patient information
• Cardular PP Uro reviews

1 INDICATIONS AND USAGE

Cardular PP Uro tablets are an alpha ₁ adrenergic antagonist indicated for :

• Signs and symptoms of Benign Prostatic Hyperplasia
• Treatment of Hypertension

1.1 Benign Prostatic Hyperplasia (BPH)

Cardular PP Uro tablets are indicated for the treatment of the signs and symptoms of BPH.

1.2 Hypertension

Cardular PP Uro tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Cardular PP Uro tablets may be used alone or in combination with other antihypertensives.

2 DOSAGE AND ADMINISTRATION

• For the treatment of BPH: Initiate therapy at 1 mg once daily. Dose maybe titrated at 1 to 2 week intervals, up to 8 mg once daily.
• For the treatment of hypertension: Initiate therapy at 1 mg once daily. Dose may be titrated as needed, up to 16 mg once daily. ( 2.3)

2.1 Dosing Information

Following the initial dose and with each dose increase of Cardular PP Uro tablets, monitor blood pressure for at least 6 hours following administration. If Cardular PP Uro tablets administration is discontinued for several days, therapy should be restarted using the initial dosing regimen.

2.2 Benign Prostatic Hyperplasia

The recommended initial dosage of Cardular PP Uro tablets is 1 mg given once daily either in the morning or evening.

Depending on the individual patient’s urodynamics and BPH symptomatology, the dose may be titrated at 1 to 2 week intervals to 2 mg, and thereafter to 4 mg and 8 mg once daily. The maximum recommended dose for BPH is 8 mg once daily.

Routinely monitor blood pressure in these patients.

2.3 Hypertension

The initial dosage of Cardular PP Uro tablets is 1 mg given once daily. Daily dosage may be doubled up 16 mg once daily, as needed, to achieve the desired reduction in blood pressure.

3 DOSAGE FORMS AND STRENGTHS

Cardular PP Uro Tablets, USP are available containing Cardular PP Uro mesylate, USP equivalent to 1 mg, 2 mg, 4 mg or 8 mg of Cardular PP Uro.

• The 1 mg tablets are white to off-white, round tablets debossed with M over D9 on one side of the tablet and scored on the other side.
• The 2 mg tablets are pink, round tablets debossed with M over D10 on one side of the tablet and scored on the other side.
• The 4 mg tablets are blue, round tablets debossed with M over D11 on one side of the tablet and scored on the other side.
• The 8 mg tablets are purple, round tablets debossed with M over D12 on one side of the tablet and scored on the other side.

• Tablets: 1 mg, 2 mg, 4 mg, 8 mg.

4 CONTRAINDICATIONS

The use of Cardular PP Uro tablets is contraindicated in patients with a hypersensitivity to Cardular PP Uro, other quinazolines (e.g., prazosin, terazosin), or any of its components.

• Hypersensitivity to Cardular PP Uro, other quinazolines, or any other ingredient in Cardular PP Uro tablets. ( 4)

5 WARNINGS AND PRECAUTIONS

• Postural hypotension with or without syncope may occur.
• Risk of Intraoperative Floppy Iris Syndrome during cataract surgery. ( 5.2)
• Screen for the presence of prostate cancer prior to treatment for BPH and at regular intervals afterwards. ( 5.3)

5.1 Postural Hypotension

Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of Cardular PP Uro tablets. However, infrequently, symptomatic postural hypotension has also been reported later than a few hours after dosing. As with other alpha-blockers, there is a potential for syncope, especially after the initial dose or after an increase in dosage strength. Advise patient how to avoid symptoms resulting from postural hypotension and what measures to take should they develop.

Concomitant administration of Cardular PP Uro tablets with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension.

5.2 Cataract Surgery

Intraoperative Floppy Iris Syndrome has been observed during cataract surgery in some patients on or previously treated with alpha ₁ blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha ₁ blocker therapy prior to cataract surgery.

5.3 Prostate Cancer

Carcinoma of the prostate causes many of the symptoms associated with BPH and the two disorders frequently co-exist. Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with Cardular PP Uro tablets for the treatment of BPH.

5.4 Priapism

Alpha ₁ antagonists, including Cardular PP Uro, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). This condition can lead to permanent impotence if not promptly treated.

6 ADVERSE REACTIONS

The most commonly reported adverse reactions from clinical trials are fatigue, malaise, hypotension, and dizziness.

To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Benign Prostatic Hyperplasia

The incidence of adverse events has been ascertained from worldwide clinical trials in 965 BPH patients. The incidence rates presented below (Table 2) are based on combined data from seven placebo-controlled trials involving once-daily administration of Cardular PP Uro tablets in doses of 1 mg to 16 mg in hypertensives and 0.5 mg to 8 mg in normotensives. Adverse reactions occurring more than 1% more frequently in BPH patients treated with Cardular PP Uro tablets versus placebo are summarized in Table 1.

Other adverse reactions occurring less than 1% more frequently in BPH patients treated with Cardular PP Uro tablets versus placebo but plausibly related to Cardular PP Uro tablets include: palpitations.

Hypertension

Cardular PP Uro tablets have been administered to approximately 4000 hypertensive patients in clinical trials, of whom 1679 were included in the hypertension clinical development program. In placebo-controlled studies, adverse events occurred in 49% and 40% of patients in the Cardular PP Uro and placebo groups, respectively, and led to discontinuation in 2% of patients in each group.

Adverse reactions occurring more than 1% more frequently in hypertensive patients treated with Cardular PP Uro tablets versus placebo are summarized in Table 1. Postural effects and edema appeared to be dose-related. The prevalence rates presented below are based on combined data from placebo-controlled studies involving once-daily administration of Cardular PP Uro at doses ranging from 1 mg to 16 mg.

Other adverse reactions occurring less than 1% more frequently in hypertensive patients treated with Cardular PP Uro tablets versus placebo but plausibly related to Cardular PP Uro tablets use include vertigo, hypotension, hot flushes, epistaxis and oedema.

Cardular PP Uro tablets have been associated with decreases in white blood cell counts.

Laboratory Changes Observed in Clinical Studies

Leukopenia/Neutropenia

Decreases in mean white blood cell and mean neutrophil count were observed in controlled clinical trials of hypertensive patients receiving Cardular PP Uro tablets. In cases where follow-up was available, WBC and neutrophil counts returned to normal after discontinuation of Cardular PP Uro tablets. No patients became symptomatic as a result of the low WBC or neutrophil counts.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Cardular PP Uro tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In postmarketing experience, the following additional adverse reactions have been reported:

Blood and Lymphatic System Disorders: leukopenia, thrombocytopenia;

Immune System Disorders: allergic reaction;

Nervous System Disorders: hypoesthesia;

Eye Disorders: Intraoperative Floppy Iris Syndrome [see Warnings and Precautions (5.2) ];

Cardiac Disorders: bradycardia;

Respiratory, Thoracic and Mediastinal Disorders: bronchospasm aggravated;

Gastrointestinal Disorders: vomiting;

Hepatobiliary Disorders: cholestasis, hepatitis cholestatic;

Skin and Subcutaneous Tissue Disorders: urticaria;

Musculoskeletal and Connective Tissue Disorders: muscle cramps, muscle weakness;

Renal and Urinary Disorders: hematuria, micturition disorder, micturition frequency, nocturia;

Reproductive System and Breast Disorders: gynecomastia, priapism.

7 DRUG INTERACTIONS

• Strong cytochrome P450 3A inhibitors may increase exposure to Cardular PP Uro and increased risk of hypotension ( 7.1)
• Concomitant administration of Cardular PP Uro tablets with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension. ( 7.2)

7.1 CYP3A Inhibitors

In vitro studies suggest that Cardular PP Uro is a substrate of CYP3A4. Strong CYP3A inhibitors may increase exposure to Cardular PP Uro. Monitor blood pressure and for symptoms of hypotension when Cardular PP Uro tablets are used concomitantly with strong CYP3A inhibitors .

7.2 Phosphodiesterase-5 Inhibitors

Concomitant administration of Cardular PP Uro tablets with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension. Monitor blood pressure and for symptoms of hypotension .

8 USE IN SPECIFIC POPULATIONS

• Hepatic Impairment: Monitor for hypotension.

8.1 Pregnancy

Risk Summary

The limited available data with Cardular PP Uro tablets in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. However, untreated hypertension during pregnancy can result in increased maternal risks . In animal reproduction studies, no adverse developmental effects were observed when Cardular PP Uro was orally administered to pregnant rabbits and rats during the period of organogenesis at doses of up to 41 mg/kg and 20 mg/kg, respectively. A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications. Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Data

Animal Data

Radioactivity was found to cross the placenta following oral administration of labelled Cardular PP Uro to pregnant rats. Studies in pregnant rabbits and rats at daily oral doses of up to 41 mg/kg and 20 mg/kg, respectively, have revealed no evidence of adverse developmental effects. A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival. In peri- and postnatal studies in rats, postnatal development at maternal doses of 40 mg/kg/day or 50 mg/kg/day of Cardular PP Uro (about 8 times human AUC exposure with a 12 mg/day therapeutic dose) was delayed, as evidenced by slower body weight gain and slightly later appearance of anatomical features and reflexes.

8.2 Lactation

Risk Summary

There is limited information on the presence of Cardular PP Uro in human milk . There is no information on the effects of Cardular PP Uro on the breastfed infant or the effects on milk production.

Data

A single case study reports that Cardular PP Uro is present in human milk, which resulted in an infant dose of less than 1% of the maternal weight-adjusted dosage and a milk/plasma ratio of 0.1. However, these data are insufficient to confirm the presence of Cardular PP Uro in human milk.

8.4 Pediatric Use

The safety and effectiveness of Cardular PP Uro tablets have not been established in children.

8.5 Geriatric Use

Benign Prostatic Hyperplasia

The safety and effectiveness profile of Cardular PP Uro tablets was similar in the elderly (age ≥ 65 years) and younger (age < 65 years) patients.

Hypertension

Clinical studies of Cardular PP Uro tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

Cardular PP Uro tablets are extensively metabolized in the liver. Hepatic impairment is expected to increase exposure to Cardular PP Uro. Use of Cardular PP Uro tablets in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. Monitor blood pressure and for symptoms of hypotension in patients with lesser degrees of hepatic impairment (Child-Pugh Class A and B) .

10 OVERDOSAGE

Experience with Cardular PP Uro tablets overdosage is limited. Two adolescents, who each intentionally ingested 40 mg Cardular PP Uro tablets with diclofenac or acetaminophen, were treated with gastric lavage with activated charcoal and made full recoveries. A two-year-old child who accidently ingested 4 mg Cardular PP Uro tablets was treated with gastric lavage and remained normotensive during the five-hour emergency room observation period. A six-month-old child accidentally received a crushed 1 mg tablet of Cardular PP Uro tablets and was reported to have been drowsy. A 32-year-old female with chronic renal failure, epilepsy, and depression intentionally ingested 60 mg Cardular PP Uro tablets (blood level = 0.9 mcg/mL; normal values in hypertensives = 0.02 mcg/mL); death was attributed to a grand mal seizure resulting from hypotension. A 39-year-old female who ingested 70 mg Cardular PP Uro tablets, alcohol, and Dalmane ^® (flurazepam) developed hypotension which responded to fluid therapy.

The oral LD ₅₀ of Cardular PP Uro is greater than 1000 mg/kg in mice and rats. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of fluid. As Cardular PP Uro is highly protein bound, dialysis would not be indicated.

11 DESCRIPTION

Cardular PP Uro tablets, USP are a quinazoline compound that is a selective inhibitor of the alpha ₁ subtype of alpha-adrenergic receptors. The chemical name of Cardular PP Uro mesylate is 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine monomethanesulfonate. The molecular formula for Cardular PP Uro mesylate is C ₂₃H ₂₅N ₅O ₅ - CH ₄O ₃S and the molecular weight is 547.6. It has the following structure:

Cardular PP Uro mesylate, USP is freely soluble in dimethylsulfoxide, soluble in dimethylformamide, slightly soluble in methanol, ethanol, and water (0.8% at 25°C), and very slightly soluble in acetone and methylene chloride. Cardular PP Uro tablets are available as colored tablets for oral use and contain 1 mg (white to off-white), 2 mg (pink), 4 mg (blue) and 8 mg (purple) of Cardular PP Uro as the free base.

The inactive ingredients for all tablets are: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate (potato). The 2 mg tablets also contain D&C Red No. 30 Aluminum Lake, the 4 mg tablets also contain FD&C Blue No. 2 Aluminum Lake, and the 8 mg tablets also contain D&C Red No. 30 Aluminum Lake and FD&C Blue No. 2 Aluminum Lake.

Cardular PP Uro Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Benign Prostatic Hyperplasia

The symptoms associated with benign prostatic hyperplasia (BPH), such as urinary frequency, nocturia, weak stream, hesitancy, and incomplete emptying are related to two components, anatomical (static) and functional (dynamic). The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component of BPH is associated with an increase in smooth muscle tone in the prostate and bladder neck. The degree of tone in this area is mediated by the alpha ₁ adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule and bladder neck. Blockade of the alpha ₁ receptor decreases urethral resistance and may relieve the obstruction and BPH symptoms and improve urine flow.

Hypertension

The mechanism of action of Cardular PP Uro tablets is selective blockade of the alpha ₁ subtype of adrenergic receptors. Studies in normal human subjects have shown that Cardular PP Uro competitively antagonized the pressor effects of phenylephrine (an alpha ₁ agonist) and the systolic pressor effect of norepinephrine. Cardular PP Uro and prazosin have similar abilities to antagonize phenylephrine. The antihypertensive effect of Cardular PP Uro tablets results from a decrease in systemic vascular resistance. The parent compound Cardular PP Uro is primarily responsible for the antihypertensive activity. The low plasma concentrations of known active and inactive metabolites of Cardular PP Uro (2-piperazinyl, 6'- and 7'-hydroxy and 6- and 7-O-desmethyl compounds) compared to parent drug indicate that the contribution of even the most potent compound (6'-hydroxy) to the antihypertensive effect of Cardular PP Uro in man is probably small. The 6'- and 7'-hydroxy metabolites have demonstrated antioxidant properties at concentrations of 5 µM, in vitro.

12.2 Pharmacodynamics

Benign Prostatic Hyperplasia

Administration of Cardular PP Uro tablets to patients with symptomatic BPH resulted in a statistically significant improvement in maximum urinary flow rate .

Effect on Normotensive Patients with Benign Prostatic Hyperplasia

Although blockade of alpha ₁ adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular resistance, Cardular PP Uro tablets treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effect (Table 4). The proportion of normotensive patients with a sitting systolic blood pressure less than 90 mmHg and/or diastolic blood pressure less than 60 mmHg at any time during treatment with Cardular PP Uro tablets 1 mg to 8 mg once daily was 6.7% with Cardular PP Uro and not significantly different (statistically) from that with placebo (5%).

Hypertension

Administration of Cardular PP Uro tablets results in a reduction in systemic vascular resistance. In patients with hypertension, there is little change in cardiac output. Maximum reductions in blood pressure usually occur 2 to 6 hours after dosing and are associated with a small increase in standing heart rate. Like other alpha ₁-adrenergic blocking agents, Cardular PP Uro has a greater effect on blood pressure and heart rate in the standing position.

12.3 Pharmacokinetics

Absorption

After oral administration of therapeutic doses, peak plasma levels of Cardular PP Uro tablets occur at about 2 to 3 hours. Bioavailability is approximately 65%, reflecting first-pass metabolism of Cardular PP Uro by the liver. The effect of food on the pharmacokinetics of Cardular PP Uro tablets was examined in a crossover study with twelve hypertensive subjects. Reductions of 18% in mean maximum plasma concentration and 12% in the area under the concentration-time curve (AUC) occurred when Cardular PP Uro tablets were administered with food. Neither of these differences is clinically significant.

In a crossover study in 24 normotensive subjects, the pharmacokinetics and safety of Cardular PP Uro were shown to be similar with morning and evening dosing regimens. The AUC after morning dosing was, however, 11% less than that after evening dosing and the time to peak concentration after evening dosing occurred significantly later than that after morning dosing (5.6 versus 3.5 hours).

Distribution

At the plasma concentrations achieved by therapeutic doses, approximately 98% of the circulating drug is bound to plasma proteins.

Metabolism

Cardular PP Uro tablets are extensively metabolized in the liver, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety. In vitro studies suggest that the primary pathway for elimination is via CYP3A4; however, CYP2D6 and CYP2C9 metabolic pathways are also involved to a lesser extent. Although several active metabolites of Cardular PP Uro have been identified, the pharmacokinetics of these metabolites have not been characterized.

Excretion

Plasma elimination of Cardular PP Uro is biphasic, with a terminal elimination half-life of about 22 hours. Steady-state studies in hypertensive patients given Cardular PP Uro doses of 2 mg to 16 mg once daily showed linear kinetics and dose proportionality. In two studies, following the administration of 2 mg orally once daily, the mean accumulation ratios were 1.2 and 1.7. Enterohepatic recycling is suggested by secondary peaking of plasma Cardular PP Uro concentrations.

In a study of two subjects administered radiolabelled Cardular PP Uro 2 mg orally and 1 mg intravenously on two separate occasions, approximately 63% of the dose was eliminated in the feces and 9% of the dose was found in the urine. On average only 4.8% of the dose was excreted as unchanged drug in the feces and only a trace of the total radioactivity in the urine was attributed to unchanged drug.

Specific Populations

Geriatric

The pharmacokinetics of Cardular PP Uro tablets in young and elderly (≥ 65 years) subjects were similar for plasma half-life values and oral clearance.

Renal Impairment

Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterations compared to younger patients with normal renal function.

Hepatic Impairment

Administration of a single 2 mg dose to patients with cirrhosis showed a 40% increase in exposure to Cardular PP Uro. The impact of moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment on the pharmacokinetics of Cardular PP Uro is not known .

Drug Interactions

There are only limited data on the effects of drugs known to influence the hepatic metabolism of Cardular PP Uro (e.g., cimetidine).

Cimetidine

In healthy volunteers, the administration of a single 1 mg dose of Cardular PP Uro on day 1 of a four-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of Cardular PP Uro, and a slight but not significant increase in mean C _max and mean half-life of Cardular PP Uro.

In vitro data in human plasma indicate that Cardular PP Uro tablets have no effect on protein binding of digoxin, warfarin, phenytoin, or indomethacin.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis: Chronic dietary administration of Cardular PP Uro mesylate at maximally tolerated doses of 40 mg/kg/day in rats and 120 mg/kg/day in mice revealed no evidence of carcinogenic potential. The highest doses evaluated in the rat and mouse studies are associated with AUCs (a measure of systemic exposure) that are 8 times and 4 times, respectively, the human AUC at a dose of 16 mg/day.

Mutagenicity studies revealed no drug- or metabolite-related effects at either chromosomal or subchromosomal levels.

Fertility in Males

Studies in rats showed reduced fertility in males treated with Cardular PP Uro at oral doses of 20 mg/kg/day (but not 5 mg/kg/day or 10 mg/kg/day), about 4 times the AUC exposures obtained with a 12 mg/day human dose. This effect was reversible within two weeks of drug withdrawal. There have been no reports of any effects of Cardular PP Uro on male fertility in humans.

13.2 Animal Toxicology and Pharmacology

An increased incidence of myocardial necrosis or fibrosis was observed in long-term (6 to 12 months) studies in rats and mice (exposure 8 times human AUC exposure in rats and somewhat equivalent to human C _max exposure in mice). Findings were not seen at lower doses. In dogs no cardiotoxicity was observed following 12 months of oral dosing at doses that resulted in maximum plasma concentrations (C _max) 14 times the C _max exposure in humans receiving a 12 mg/day therapeutic dose or in Wistar rats at C _max exposures 15 times human C _max exposure. There is no evidence that similar lesions occur in humans.

14 CLINICAL STUDIES

14.1 Benign Prostatic Hyperplasia

The efficacy of Cardular PP Uro tablets was evaluated extensively in over 900 patients with BPH in double-blind, placebo-controlled trials. Cardular PP Uro tablets treatment was superior to placebo in improving patient symptoms and urinary flow rate. Significant relief with Cardular PP Uro tablets was seen as early as one week into the treatment regimen, with Cardular PP Uro tablets-treated patients (N = 173) showing a significant (p < 0.01) increase in maximum flow rate of 0.8 mL/sec compared to a decrease of 0.5 mL/sec in the placebo group (N = 41). In long-term studies, improvement was maintained for up to 2 years of treatment. In 66% to 71% of patients, improvements above baseline were seen in both symptoms and maximum urinary flow rate.

In three placebo-controlled studies of 14 to 16 weeks’ duration, obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning) of BPH were evaluated at each visit by patient-assessed symptom questionnaires. The bothersomeness of symptoms was measured with a modified Boyarsky questionnaire. Symptom severity/frequency was assessed using a modified Boyarsky questionnaire or an AUA-based questionnaire. Uroflowmetric evaluations were performed at times of peak (2 to 6 hours post-dose) and/or trough (24 hours post-dose) plasma concentrations of Cardular PP Uro tablets.

The results from the three placebo-controlled studies (N = 609) showing significant efficacy with 4 mg and 8 mg Cardular PP Uro are summarized in Table 3. In all three studies, Cardular PP Uro tablets resulted in statistically significant relief of obstructive and irritative symptoms compared to placebo. Statistically significant improvements of 2.3 mL/sec to 3.3 mL/sec in maximum flow rate were seen with Cardular PP Uro tablets in Studies 1 and 2, compared to 0.1 mL/sec to 0.7 mL/sec with placebo.

In one fixed-dose study (Study 2), Cardular PP Uro tablets therapy (4 mg to 8 mg, once daily) resulted in a significant and sustained improvement in maximum urinary flow rate of 2.3 mL/sec to 3.3 mL/sec (Table 3) compared to placebo (0.1 mL/sec). In this study, the only study in which weekly evaluations were made, significant improvement with Cardular PP Uro tablets versus placebo was seen after one week. The proportion of patients who responded with a maximum flow rate improvement of ≥ 3 mL/sec was significantly larger with Cardular PP Uro tablets (34% to 42%) than placebo (13% to 17%). A significantly greater improvement was also seen in average flow rate with Cardular PP Uro tablets (1.6 mL/sec) than with placebo (0.2 mL/sec). The onset and time course of symptom relief and increased urinary flow from Study 1 are illustrated in Figure 1.

Table 3. Summary of Effectiveness Data in Placebo-Controlled Trials Figure 1 - Study 1

14.2 Hypertension

In a pooled analysis of placebo-controlled hypertension studies with about 300 hypertensive patients per treatment group, Cardular PP Uro, at doses of 1 mg to 16 mg given once daily, lowered blood pressure at 24 hours by about 10/8 mmHg compared to placebo in the standing position and about 9/5 mmHg in the supine position. Peak blood pressure effects (1 to 6 hours) were larger by about 50% to 75% (i.e., trough values were about 55% to 70% of peak effect), with the larger peak-trough differences seen in systolic pressures. There was no apparent difference in the blood pressure response of Caucasians and blacks or of patients above and below age 65. In the same patient population, patients receiving Cardular PP Uro tablets gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients.

16 HOW SUPPLIED/STORAGE AND HANDLING

Cardular PP Uro Tablets, USP are available as tablets for oral administration. Each tablet contains Cardular PP Uro mesylate, USP equivalent to 2 mg of Cardular PP Uro.

The 2 mg tablets are pink, round tablets debossed with M over D10 on one side of the tablet and scored on the other side. They are available as follows:

Bottles of 90 tablets.

Recommended Storage: Store at 20° to 25°C (68° to 77°F).

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Patient Information Leaflet with each prescription.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling ( Patient Information).

Postural Hypotension: Advise patients of the possibility of syncopal and orthostatic symptoms, especially at the initiation of therapy, and urged to avoid driving or hazardous tasks for 24 hours after the first dose, after a dosage increase, and after interruption of therapy when treatment is resumed. Advise patients to report symptoms to their healthcare provider.

Priapism: Advise patients of the possibility of priapism and to seek immediate medical attention if symptoms occur.

Patient Information

The brands listed are trademarks of their respective owners.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Revised: 7/2017

DXZN:R11ppb/PL:DXZN:R7ppb

Cardular PP Uro pharmaceutical active ingredients containing related brand and generic drugs:

• Doxazosin Mesylate

Cardular PP Uro available forms, composition, doses:

• Tablets, Modified Release; Oral; Doxazosin Mesylate 4 mg

Cardular PP Uro destination | category:

• Human:
• Alpha-adrenergic blocking agents
• Antihypertensives
• Drugs for bladder and prostate disorders

Cardular PP Uro Anatomical Therapeutic Chemical codes:

• C02CA04 - Doxazosin

Cardular PP Uro pharmaceutical companies:

• Pfizer

References

1. Dailymed."DOXAZOSIN (DOXAZOSIN MESYLATE) TABLET [PD-RX PHARMACEUTICALS, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. "doxazosin". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
3. "doxazosin". http://www.drugbank.ca/drugs/DB0059... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Cardular PP Uro after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Cardular PP Uro not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology